Abstract
Cancer remains an elusive killer due, in part, to the suppression of normal immunologic antitumor responses. Normal host (NH) macrophage (Mf) populations have tumoricidal effects such as tumor antigen phagocytosis and presentation, and cytokine production. Tumor-infiltrating Mfs may evade these activities by dysregulating production of immunostimulatory cytokines (including Interleukin [IL]-1b, IL-18, and tumor necrosis factor-a [TNF-a]), by production of antagonistic factors. The restoration of IL-1b, IL-18, and TNF-a production by Mfs could re-establish antitumor host immune responses. Tumor distal (TD) Mfs produce more IL-1b than NH Mfs. IL-1b production was downregulated among in situ TP Mfs likely because immunomodulatory factors like IL-10 and tumor growth factor–b were present. IL-18, a structural homologue to IL-1b was similarly dysregulated in TD and TP Mfs. IL-18 was enhanced in both distal and proximal Mfs. TNF-a followed the dysregulation pattern of IL-1b in our tumor-burdened hosts (TBH), likely because of the similar functions of these cytokines. As a potential vehicle for immunotherapeutic treatment, paclitaxel’s action on the immune response (TAXOL™) was investigated. Paclitaxel is a Mf activator that enhanced TD Mf production of IL-1b, IL-18, and TNF-a. Production of IL-1b and TNF-a was reduced in TP Mfs when treated with paclitaxel; however, IL-18 production was enhanced. These cytokines induce production of the tumoricidal molecules IL-12 and nitric oxide (NO). Paclitaxel treatment enhanced NO production distally, but not proximally. IL-12 was produced by NH and TD Mfs. Collectively, these studies suggest that tumor-induced cytokine imbalances compromise antitumor immunity and paclitaxel may reverse this activity.
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